Lymphocytic Leukemia and HbA1c Measurement

Mechanism of Low HbA1c in Lymphocytic Leukemia

HbA1c values reflect glycemia over the preceding 120 days, with approximately 50% determined by blood glucose levels in the month prior to measurement, 25% from 30-60 days before, and 25% from 60-120 days before measurement 1
Any condition that shortens erythrocyte lifespan decreases HbA1c values, since glycation of hemoglobin increases with the age of red blood cells 1, 2
Chronic lymphocytic leukemia can cause hemolytic anemia or otherwise reduce red blood cell survival, leading to falsely low HbA1c readings that do not accurately reflect actual glycemic control 1, 3

Advanced CLL (Binet stage C) is characterized by anemia (hemoglobin <10 g/dl) and/or thrombocytopenia, which can affect HbA1c measurements 4

When evaluating HbA1c in patients with lymphocytic leukemia, clinicians should be aware that values may be falsely low and not representative of true glycemic control 1
A hemoglobin variant or interference should be suspected if the HbA1c reading is surprisingly low or significantly changed coincident with a change in laboratory method 1
In patients with CLL and suspected HbA1c interference, alternative methods for monitoring glycemic control should be considered, such as self-monitoring of blood glucose (SMBG) 1, fructosamine or glycated albumin measurements 3, and continuous glucose monitoring when available 1

Besides lymphocytic leukemia, other conditions that can decrease HbA1c include kidney disease 1, liver disease 1, hemolytic anemia 1, hemoglobinopathies 1, recovery from blood loss 1, and pregnancy 1
Conditions that slow erythropoiesis, such as iron-deficiency anemia and aplastic anemia, can increase HbA1c by causing an older erythrocyte cohort 1

When HbA1c values are unexpectedly low in a patient with lymphocytic leukemia, consider using a boronate affinity chromatography method of measuring HbA1c, which may be more reliable in the presence of interfering factors 1
The National Glycohemoglobin Standardization Program (NGSP) provides resources for addressing potential interferences in HbA1c testing 1
In cases of suspected interference, correlation with other glycemic measures (fasting glucose, post-prandial glucose) is essential to establish true glycemic status 1

The American Diabetes Association notes that hemolytic conditions, including hemolytic anemia, sickle cell disease, or chronic lymphocytic leukemia, reduce erythrocyte lifespan and falsely lower HbA1c 5
Recent blood loss or transfusion decreases the average age of circulating red blood cells, reducing glycation time, as reported by the American Diabetes Association 5
Erythropoietin therapy stimulates production of younger red blood cells with less accumulated glycation, according to the Endocrine Society 6
Glucose-6-phosphate dehydrogenase deficiency can lower HbA1c by approximately 0.8% in homozygous individuals through increased red cell turnover, as noted by the American Diabetes Association 5

The American Diabetes Association recommends confirming both measurements are accurate by repeating tests, ensuring FBS samples were spun and separated immediately after collection 5
Hemoglobinopathy screening, particularly in African American patients or those with family history, is recommended by the American Diabetes Association 5

The American Diabetes Association suggests using plasma glucose criteria alone to diagnose and monitor diabetes when marked discordance exists between HbA1c and plasma glucose 5
Fructosamine or glycated albumin reflect 2-4 weeks of glycemic control and are less affected by red cell turnover, as reported by the Endocrine Society 6
Serum albumin-adjusted glycated albumin may provide better accuracy in patients with hypoalbuminemia, according to the Endocrine Society 6

The American Diabetes Association notes that African Americans may have HbA1c levels 0.3-0.8% higher than non-Hispanic whites with identical glucose levels, but the reverse can occur with certain genetic variants 5
Iron deficiency anemia paradoxically increases HbA1c by creating an older red blood cell cohort, opposite to hemolytic conditions, as reported by the American Diabetes Association 5
In conditions such as active hemolysis or hemolytic anemia, pregnancy, hemodialysis, recent significant blood loss or transfusion, and erythropoietin therapy, only use plasma glucose criteria for diagnosis and monitoring, as recommended by the American Diabetes Association and the Endocrine Society 5, 6